The program outlined herein is directed at the total synthesis of a structurally diverse set of natural products, all of which exhibit cytotoxic properties. The synthetic schemes are designed to provide efficient and stereoselective routes to the target molecules in their natural absolute configurations. Our goal is to develop and apply new methods and strategies which will allow the production of significant quantities of the natural products and close structural analogs thereof for biological screening. The proposal includes synthetic sequences leading to the cytotoxic diterpenoid pseudopterodide, the neutral macrolide antibiotic and cytotoxic agent cytovaricin, the aglycones of the tumor inhibitory sesquiterpene glycosides phyllanthocide, phyllanthostatin 1, phyllanthostatin 2, and phyllanthostatin 3, and the C(1)-Alpha-hydroxylated pseudoguaianolides coronopilin, parthenin, and psilostachyin. The pseudoguaianolide proposals are being carried over from the initial grant period, of which just over two years have been expended. We anticipate that this segment will be largely completed by the 12/01/83 starting date requested in this proposal. The specific types of chemical methodology to be developed and applied include the chelation-controlled enolate Claisen rearrangement, metal- and metaloid-induced carbolactonization, asymmetric induction in pericyclic transitions states with removable chiral auxiliaries, nitrile oxide cycloadditions, and the intramolecular functionalization of Pi-allylpalladium intermediates.